Drug treatment of obesity: Current status and future prospects

Highlights

• Several antiobesity agents have been withdrawn from market due to safety concerns.

• Currently approved drugs include orlistat, lorcaserin, phentermine/topiramate, and naltrexone/bupropion.

• Several new therapies are being evaluated to address unmet safety and efficacy needs.

• Polytherapy can possibly overcome counterregulatory responses and minimize adverse effects.

Abstract

Obesity is a growing epidemic and a major contributor to the global burden of disease. Obesity strains the healthcare systems and has profound economic and psychosocial consequences. Historically, pharmacotherapy for obesity has witnessed the rise and fall of several promising drug candidates that had to be eventually withdrawn due to unacceptable safety concerns. Currently four drugs are approved for chronic weight management in obese adults: orlistat, lorcaserin, phentermine/topiramate extended release and naltrexone/bupropion extended release. While lorcaserin and phentermine/topiramate were approved by US Food and Drug Administration (FDA) in 2012, after a gap of 13 years following the licensing of orlistat, naltrexone/bupropion has been recently approved in 2014. This review provides a brief overview of these current therapeutic interventions available for management of obesity along with the evidence of their safety and efficacy. Additionally, several novel monotherapies as well as combination products are undergoing evaluation in various stages of clinical development. These therapies if proven successful will strengthen the existing armamentarium of antiobesity drugs and will be critical to combat the global public health crisis of obesity and its associated co-morbidities.

Introduction

Globally, overweight and obesity, most often defined on the basis of body mass index (BMI) measurements, are the fifth most common risk factors for death. As per World Health Organization (WHO) estimates, in 2008, more than 1.4 billion adults aged 20 and older, were overweight and among them, over 500 million were obese [1]. Recent prevalence data estimate that more than one-third of adults and 17% of youth (aged 2–19 years) in the United States are obese [2]. In the UK, between 1993 and 2011, the proportion of individuals that were overweight including obese increased from 58% to 65% in men and from 49% to 58% in women. Among them in 2011, nearly 24% men and 26% women were estimated to be obese [3]. This prevalence of obesity has been predicted to increase by 2050 to 60% of adult men, 50% of adult women and 25% of children under 16 years of age [4]. The epidemic of obesity is not limited to the developed countries but has been documented as a global phenomenon, with the proportion of obese populations rising in most countries. According to a recent report, between 1980 and 2008, the number of overweight and obese adults in developing countries has more than tripled to reach a figure in excess of 900 million adults [5].

The fundamental drivers of obesity epidemic are the global trade liberalization, rapid urbanization and economic growth. A dramatic reduction in the demand for physical activity and global nutritional transitions have created obesogenic environments. The latter are primarily driven by large scale decrease in food prices and increase in consumption of animal products, refined grains and added sugar resulting in an overall positive energy balance [6]. The chief co-morbidities associated with obesity include type II diabetes mellitus, cardiovascular diseases including myocardial infarction, stroke, hypertension, dyslipidemia, asthma, sleep apnoea, gall bladder disease, osteoarthritis, chronic neck pain and certain types of cancer [7].

Management of obesity encompasses comprehensive lifestyle modifications including dietary changes, physical activity and behaviour modification, pharmacologic therapy and bariatric surgery. Lifestyle modifications often require multidisciplinary teams to ensure necessary changes are made as well as maintained but are often associated with high relapse rates [8]. Bariatric surgery is associated with risks of peri-operative mortality and operative complications and is consequently reserved for clinically severe obesity [9]. The surgical procedures are expensive and operated individuals require lifelong medical monitoring. Given the current limitations of lifestyle modification interventions and bariatric surgery, use of pharmacotherapeutic agents in management of obesity is critical. Several antiobesity agents have been approved in the past and were touted as ‘magic pills’ for addressing the obesity epidemic. However, many of them were subsequently found to have unacceptable risks leading to their restricted use/withdrawal from the market (Table 1) [10], [11], [12], [13].

Among the currently approved antiobesity agents for chronic weight management, orlistat was approved in 1999 and subsequently after a long gap of more than a decade, two new therapies, lorcaserin and phentermine/topiramate were approved in 2012. In 2014, FDA finally approved the combination of bupropion/naltrexone as a treatment option for the management of obesity.